Angiotensin II and control of sodium and water intake in the mouse.

  • Ole Skøtt
  • Published 2003 in
    American journal of physiology. Regulatory…


A PRECISE BALANCE BETWEEN intakes and losses of water and sodium is important for the maintenance of the “milieu interieur.” Water intake is stimulated by increased plasma osmolality, by volume contraction, by a fall in blood pressure, and by high sodium concentration in the gastrointestinal tract. Volume contraction and low blood pressure activate the systemic reninangiotensin system, and a high circulating plasma ANG II concentration is a stimulus for thirst in a variety of species. Sodium appetite is stimulated by sodium deficiency, by hypovolemia, by ANG II, and by mineralocorticoids (5). Changes in plasma osmolarity and hormone concentrations are sensed by the brain at the circumventricular organs, which lack a blood-brain barrier. These include the subfornical organ (SFO) and the organum vasculosum laminae terminalis (OVLT) in the anterior third ventricle (AV3V) and the area postrema (AP) at the fourth ventricle. When activated by hyperosmolality, osmoreceptor cells in the SFO and OVLT activate neurons projecting to the paraventricular nucleus (PVN) and supraoptic nucleus (SON) in the hypothalamus to stimulate thirst and sodium appetite. For a wide variety of mammals, and especially for the rat, there is very good evidence that ANG II plays an important role for the activation of thirst and sodium appetite by activating AT1 receptors in the SFO and OVLT (5). In the mouse, the evidence for involvement of circulating ANG II in this control is more controversial. Thus systemic administration of ANG II in C57Bl/6 (6) or BALB/c mice (4, 6) does not stimulate drinking. In a recently developed transgenic mouse with aberrant production of renin in the liver, water intake was high. This would be consistent with stimulation of thirst by the circulating renin-angiotensin system, but the kidney was damaged, and it is not clear whether stimulation of thirst was a primary event (1). In a recent comprehensive review, Fitzsimons (5) concluded that increased water intake in mouse is secondary to a slowly developing increase in sodium intake. In contrast to the lack of evidence for stimulation of water and sodium appetite by peripheral ANG II, there is much better evidence for such actions of ANG II within the brain of mice. Thus ANG II increased drinking and NaCl intake after 3 days of intracerebroventricular infusion in BALB/C mice (4), and acute drinking responses were observed in 129Sv/C57Bl mice after intracerebroventricular injection of rather large ANG II doses (3). ANG II receptors (AT1a and AT1b) are present in the mouse brain in areas involved in the regulation of electrolyte and cardiovascular balance. Stimulation of thirst by 5 days of 2% NaCl led to upregulation of AT1a receptors in AV3V, PVN, and SFO (2). Conversely, in mice where the AT1 receptor genes had been knocked out, the drinking response to intracerebroventricular ANG II was more reduced in AT1b / mice than in AT1a / mice (3). The AT2 receptor has also been suggested to contribute to the dipsogenic response to ANG II (7). Double transgenic mice with brain expression of human renin and angiotensin in glia cells and neurons produce local ANG II, and these mice exhibited an increase in drinking volume and salt preference (8, 9), again pointing to stimulation of thirst and sodium appetite by ANG II within the brain. In view of the strong evidence for participation of ANG II within the brain in the control of thirst and sodium appetite in mice, the lack of a clear effect of circulating ANG II calls for an explanation. In this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Rowland and coworkers (11) set out to investigate this question in the CD1 mouse. First they injected mice with ANG I or ANG II and confirmed that these substances do not readily activate water and sodium intake. Then they asked the question whether injected ANG II is able to enter the relevant circumventricular organs and activate neurons in the OVLT and SFO. They used the immediate-early response gene c-Fos as a mapping tool to identify active nerve cells. With this technique they demonstrated that ANG II induced upregulation of c-Fos in the SFO and AP, thereby showing that ANG II had entered and activated the cells involved in activation of thirst and sodium appetite. Sodium depletion by furosemide treatment increased plasma renin activity and upregulated c-Fos in the same areas as ANG II infusion, but in this case the maneuver was associated with stimulation of salt appetite. Polyethylene glycol (PEG) increased thirst in the mice without stimulating salt appetite. This treatment, which led to hypovolemia, increased plasma renin and aldosterone concentrations and caused a general upregulation of c-Fos. The two latter series of experiments demonstrate that maneuvers, which, in fact, stimulate thirst and sodium appetite, lead to upregulation of c-Fos. Thus the experAddress for reprint requests and other correspondence: O. Skøtt, Physiology and Pharmacology, Univ. of Southern Denmark, 21, Winsløwparken DK-5000 Odense, Denmark (E-mail: Am J Physiol Regul Integr Comp Physiol 284: R1380–R1381, 2003; 10.1152/ajpregu.00106.2003.

Cite this paper

@article{Sktt2003AngiotensinIA, title={Angiotensin II and control of sodium and water intake in the mouse.}, author={Ole Sk\ott}, journal={American journal of physiology. Regulatory, integrative and comparative physiology}, year={2003}, volume={284 6}, pages={R1380-1} }